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    Summary
    EudraCT Number:2016-000704-28
    Sponsor's Protocol Code Number:GCP#05.01.020
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-06-11
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2016-000704-28
    A.3Full title of the trial
    A Multicenter, Randomized, Phase III Registration Trial of Transplantation of NiCord®, Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem and Progenitor Cells, versus Unmanipulated Umbilical Cord Blood for Patients with Hematological Malignancies
    Etude de phase III multicentrique, randomisée, en vue d'approbation, comparant la greffe de NiCord®, cellules souches et progénitrices amplifiées ex vivo à partir de sang de cordon ombilical, et la greffe de sang de cordon ombilical non manipulé chez des patients présentant une hémopathie maligne
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter trial of transplantation of NiCord, stem cells from donated umbilical cord blood that were grown in a laboratory to expand their number versus unmanipulated umbilical cord blood for patients with cancers of the blood and lymph
    Etude multicentrique comparant la greffe de NiCord, cellules souches de donneurs de sang de cordon ombilical cultivées en laboratoire pour augmenter leur nombre versus du sang de cordon ombilical non manipulé chez des patients presentant des cancers du sang et de la lymphe
    A.4.1Sponsor's protocol code numberGCP#05.01.020
    A.5.4Other Identifiers
    Name:NANumber:NA
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGamida Cell Ltd
    B.1.3.4CountryIsrael
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGamida Cell Ltd
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGamida Cell Ltd
    B.5.2Functional name of contact pointClinical trial department
    B.5.3 Address:
    B.5.3.1Street Address5, Nahum Hafzadi, Beit Ofer
    B.5.3.2Town/ cityJerusalem
    B.5.3.3Post code9548401
    B.5.3.4CountryIsrael
    B.5.4Telephone number97226595666
    B.5.5Fax number97226595616
    B.5.6E-mailIrit@gamida-cell.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1852
    D.3 Description of the IMP
    D.3.1Product nameNiCord (CF cultured fraction and NF non-cultured fraction)
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAllogeneic, ex vivo expanded, umbilical cord blood-derived, hematopoietic CD34+ progenitor cells
    D.3.9.3Other descriptive nameALLOGENEIC, EX VIVO EXPANDED, UMBILICAL CORD BLOOD-DERIVED, HEMATOPOIETIC CD34+ PROGENITOR CELLS
    D.3.9.4EV Substance CodeSUB181698
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number800000000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAllogeneic, non-expanded, umbilical cord blood-derived, hematopoietic mature myeloid and lymphoid cells
    D.3.9.3Other descriptive nameALLOGENEIC, NON-EXPANDED, UMBILICAL CORD BLOOD-DERIVED, HEMATOPOIETIC MATURE MYELOID AND LYMPHOID CELLS
    D.3.9.4EV Substance CodeSUB181699
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number400000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High risk haematological malignancies
    Hemopathie maligne a haut risque
    E.1.1.1Medical condition in easily understood language
    cancer affecting blood, bone marrow, lymph nodes
    Cancer affectant le sang, la moelle osseuse, les ganglions lymphatiques
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009015
    E.1.2Term Chronic myeloid leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028534
    E.1.2Term Myelodysplastic syndrome NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10006597
    E.1.2Term Burkitt's lymphoma NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10076434
    E.1.2Term Hepatosplenic gamma-delta T-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025315
    E.1.2Term Lymphoma malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10036889
    E.1.2Term Prolymphocytic leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073481
    E.1.2Term Enteropathy-associated T-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054481
    E.1.2Term Natural killer-cell leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054655
    E.1.2Term T-cell type acute leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10000836
    E.1.2Term Acute leukemia NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10067837
    E.1.2Term Acute biphenotypic leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054681
    E.1.2Term Undifferentiated type acute leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The overall study objective is to compare the safety and efficacy of NiCord single ex-vivo expanded cord blood unit transplantation to unmanipulated cord blood unit transplantation in patients with hematological malignancies following conditioning therapy
    L'objectif général de la recherche est la comparaison de l'innocuité et l'efficacité de la transplantation de NiCord - unité de sang de cordon amplifié ex-vivo - à une transplantation d'unité de sang de cordon non manipulé chez des patients atteints d’hémopathies malignes à la suite d'un protocole de conditionnement
    E.2.2Secondary objectives of the trial
    Not applicable - see primary and secondary endpoints sections
    Non applicable - voir les sections sur les paramètres primaires et secondaires
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. Optional Long term follow-up sub-study- For patients who received transplantation and agreed to enroll in the observational long term
    follow-up sub-study, long-term outcomes will be collected at 2 years, 3 years, 4 years and 5 years post transplantation.
    The overall research goals for this sub-study are:
    -Describe long term sustained donor chimerism
    -Describe survival and disease free survival
    -Describe characteristics of patients with secondary graft failure or disease relapse
    -Describe long term immune reconstitution
    -Describe incidence of chronic GvHD
    2.Optional supplemental immune reconstitution sub-study will explore immune biomarkers potentially predicting clinical outcomes such as relapse, engraftment and viral reactivation/disease. Blood samples
    for exploratory research of immune reconstitution will be collected from the patients who consent to this sub-study for immunophenotyping and MultiPlex analyses (on days 7, 14, 21, 28, 42, 56, 70, 100, 180, and day 365 visits) as well as for T cell receptor analysis (at screening and on days 100, 180 and 365 visits). These samples will be sent to a central laboratory for analysis as detailed in a separate research study plan.
    1. Sous-étude facultative de suivi à long terme - Pour les patients qui ont reçu une
    greffe et ont accepté de s'inscrire au programme d'observation à long terme, les résultats à long terme seront collectés à 2 ans, 3
    ans, 4 ans et 5 ans après la transplantation.
    Les objectifs généraux de recherche pour cette sous-étude sont les suivants:
    -Décrire le chimérisme prolongé des donneurs
    -Décrire la survie et la survie sans maladie
    -Décrire les caractéristiques des patients présentant un échec de greffe
    secondaire ou une rechute
    -Décrire la reconstitution immunitaire à long terme
    -Décrire l'incidence de la GvHD chronique
    2.La sous-étude supplémentaire facultative sur la reconstitution immunitaire explorera des biomarqueurs immunitaires anticipant potentiellement des résultats cliniques tels que rechute, greffe et réactivation / maladie virale. Des échantillons de sang
    pour la recherche exploratoire de la reconstitution immunitaire seront recueillis chez
    les patients qui ont consenti à cette sous-étude pour
    immunophénotypage et Analyses MultiPlex (aux visites des jours 7, 14, 21, 28, 42, 56, 70, 100, 180 et 365) ainsi que pour l'analyse des récepteurs des lymphocytes T (au dépistage et aux visites des jours 100, 180 et 365). Ces échantillons seront envoyés à un laboratoire centrale pour analyse détaillée dans un plan d'étude distinct.
    E.3Principal inclusion criteria
    1.12-65 years of age
    2.Patients with one of the following HM (or according to
    local guidelines/recommendations if these are more stringent) : Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), CMMoL or MDS/CMMoL overlap, Myelodysplastic Syndrome (MDS) and Lymphoma as defined in the protocol. Biphenotypic/undifferentiated/Prolymphocytic/Dendritic Cell Leukemias and Natural Killer Cell Malignancies in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR. Patients with CLL are not eligible regardless of disease status.
    3.CBU criteria as described in the protocol;
    4.Patients who will be starting conditioning prior to NiCord release for infusion (i.e., NiCord arrival on site in adequate condition) must have an additional partially HLA-matched CBU reserved as a BU to the NiCord arm in case of production failure. The BU CBU must be HLA-matched at 4-6/6 HLA class I(HLA-A&HLA-B, low resolution) and
    II (HLA-DRB1,high resolution) loci with the patient. A second BU CBU is recommended to be added in the below cases: If the BU CBU is HLA matched at 5-or 6/6, and contains a pre-cryopreserved total nucleated cell dose of<2.5x10^7 TNC/kg, OR a pre-cryopreserved CD34+ cell dose
    of<1.2 x10^5CD34+ cells/kg. If the BU CBU is HLA-matched at 4/6, and contains a pre-cryopreserved total nucleated cell dose of<3.5x10^7 TNC/kg, OR a pre cryopreserved CD34+ cell dose of
    <1.7x10^5CD34+cells/kg. In case of two BU CBUs, the second BU CBU must also be HLA-matched at 4-6/6 HLA class I(HLA-A&HLA-B, low resolution) and II (HLA-DRB1,high resolution) loci with the patient. The BU CBUs are recommended to have a combined pre-cryopreserved total
    nucleated cell dose of at least 3x10^7 TNC/kg.
    5.Patient's Performance score ≥70% by Karnofsky or Lansky
    6. Patient has sufficient physiologic reserves including: a.Cardiac: LVEF of ≥40% by echocardiogram, radionuclide scan or cardiac MRI or Left
    ventricular shortening fraction ≥ 29%. b.PFT demonstrating FVC and FEV1 of >50% of predicted for age and cDLCO>50% of predicted for
    patients in whom pulmonary function testing can be performed c.Renal: Creatinine clearance test ≥60mL/min d.Hepatic: Serum Bilirubin<2.0
    mg/dl; Hepatic transaminases<3xupper limit of normal range
    7.Females of childbearing potential, defined as any female who has experienced menarche and is not postmenopausal or permanently sterilized, agree to use an appropriate method of contraception from at least 7 days prior to conditioning regimen therapy until completion of FU
    procedures.
    8.Patient signs the written informed consent after being aware of the nature of the patient's disease and willingly consents to the treatment program after being informed of alternative treatments,
    potential risks, benefits, and discomforts
    1.âgés de 12 à 65 ans
    2.Patients ayant une des hémopathies malignes suivantes (ou selon les directives / recommandations locales si elles sont plus strictes) : Leucémie aiguë lymphoblastique (LAL), Leucémie aiguë myéloïde (LAM), Leucémie myéloïde chronique (LMC), CMMoL ou chevauchement SMD / CMMoL, Syndrome myélodysplasique (SMD) et lymphome comme definis dans le protocol. Leucémies à cellules biphénotypiques/ non différenciées/ prolymphocytaires/ dendritiques et tumeurs malignes à cellules tueuses naturelles dans la première RC ou les suivantes, leucémie/lymphome à cellules T adultes dans la première RC ou les suivantes. Les patients atteints de LLC ne sont pas admissibles quel que soit leur état pathologique.
    3. Les criteres d'USC tels que definis dans le protocol.
    4. Les patients qui commenceront le conditionnement avant la libération de NiCord pour perfusion (c.-à-d. l'arrivée de NiCord sur place dans un état adéquat) doivent avoir une USC supplémentaire compatible HLA en tant qu’unité de secours dans le bras NiCord en cas d'échec de production de NiCord. L’USC de secours doit être compatible à 4-6/6 aux loci HLA de classe I (HLA-A & HLA-B, basse résolution) et classe II (HLA-DRB1, haute résolution) avec le patient. Il est recommandé d'ajouter une deuxième USC de secours dans les cas suivants: Si l’USC de secours est compatible HLA à 5 ou 6/6, et contient une dose de cellules nucléées totales avant la cryopréservation (post-traitement) <2,5 x 10^7 CNT/kg, ou une dose cellulaire pré-cryopréservée (post-traitement) de CD34+ <1,2 x 10^5 CD34+ cellules/kg. If the back-up CBU is HLA-matched at 4/6, and contains a pre-cryopreserved (post processing) total nucleated cell dose of <3.5x10^7 TNC/kg, OR a pre-cryopreserved (post processing) CD34+ cell dose of <1.7 x10^5 CD34+ cells/kg. Dans le cas de deux USCs de secours, la deuxième USC de secours doit aussi être compatible à 4-6/6 aux loci HLA de classe I (HLA-A & HLA-B, basse résolution) et classe II (HLA-DRB1, haute résolution) avec le patient. Il est recommandé que les USCs de secours aient une dose combinée de cellules nucléées totales pré-cryopréservées (post-traitement) d'au moins 3 x 10^7 CNT/kg.
    5. Score de performance du patient ≥70 % par Karnofsky ou Lansky
    6. Le patient a des réserves physiologiques suffisantes, notamment: a.Cardiaque:(FEVG) ≥40 % par échocardiographie, balayage du radionucléide ou IRM cardiaque, ou fraction de raccourcissement ventriculaire gauche ≥ 29 %. b. fonction pulmonaire démontrant que la CVF et le VEMS sont supérieurs à 50 % des valeurs prédites pour l'âge et que le cDLCO est supérieur à 50 % des valeurs prédites pour les patients chez qui des tests de la fonction pulmonaire peuvent être effectués. c.Rénale: test de clairance de la créatinine ≥60 mL / min. d.Hépatique: Bilirubine sérique < 2,0 mg/ dl ; transaminases hépatiques < 3x limite supérieure de la normale.
    7. Les femmes en âge de procréer, c'est-à-dire celles qui ont déjà eu des règles et qui n'ont pas été ménopausées ou qui n'ont pas été stérilisées de façon permanente, acceptent d'utiliser une méthode de contraception appropriée à partir d'au moins 7 jours avant le protocole de conditionnement jusqu'à la fin des procédures de suivi.
    8. Le patient signe le consentement éclairé écrit après avoir été informé de la nature de la maladie du patient et avoir consenti volontairement au programme de traitement après avoir été informé des alternatives à ce traitement, des risques potentiels, des avantages et des inconforts.
    E.4Principal exclusion criteria
    1.MDS or CML with "marked" or "3+" fibrosis
    2. CLL
    3.Fewer than 21 days have elapsed since initiation of the patient's last
    chemotherapy cycle and the initiation of the stem cell transplant
    preparative regimen (radiotherapy,intrathecal agents, hydroxyurea,
    tyrosine kinase inhibitors, hypomethylating agents, rituximab, blinatumomab and
    lenalidomide are not considered chemotherapy)
    4.Persistent clinically significant toxicities that, in the investigator's
    opinion, make the patient unsuitable for transplant
    5.Evidence of donor specific anti-HLA antibodies to the selected
    treatment CBU #1 (MFI>3000 to HLA A, B, C, or DRB1)
    6.Evidence of HIV infection or HIV positive serology
    7.Evidence of active Hepatitis B or Hepatitis C as determined by serology
    or PCR
    8.Pregnancy, as indicated by a positive serum or urine human chorionic
    gonadotrophin (HCG) test, or lactation
    9.Active malignancy other than that for which the UCB transplant is being performed within 12 months of enrollment. Fully resected
    cutaneous squamous cell or basal cell carcinoma or cervical carcinoma in
    situ within 12 months of enrollment will be permitted.
    10.Evidence of uncontrolled bacterial, fungal or viral infections or severe
    concomitant diseases, which in the judgment of the Principal
    investigator indicate that the patient could not tolerate transplantation
    11.Patients with presence of leukemic blasts in the central nervous
    system (CNS)
    12.Patients with an 8/8 allele level HLA-matched (or according to local guidelines/recommendations if these are more stringent) and readily available
    related or unrelated donor (whose stem cells can be collected in a timely
    manner without jeopardizing recipient outcome). Patients who have
    haploidentical related donors or syngeneic donors will not be excluded
    13.Prior allogeneic hematopoietic stem cell transplant
    14.Allergy to bovine products, gentamicin, or to any other product that
    may interfere with the treatment
    15.Psychologically incapable of undergoing bone marrow transplant
    (BMT) with associated strict isolation or documented history of medical
    non-compliance and/or psychiatric illness and/or social situations that
    would limit compliance with study requirements
    16.Enrolled in another interventional clinical trial or received an
    investigational treatment within 30 days prior to the approved date of
    randomization, unless documented approval obtained from Sponsor prior
    to the anticipated date of randomization, unless documented approval
    obtained from Sponsor prior to randomization
    1. SMD ou LMC avec fibrose "marquée" ou "3+"
    2. LLC
    3. Moins de 21 jours se sont écoulés entre le début du dernier cycle de chimiothérapie du patient et le début du traitement préparatoire à la greffe de cellules souches (radiothérapie, agents intrathécaux, hydroxyurée, inhibiteurs de tyrosine kinase, agents hypométhylants, rituximab, blinatumomab et lénalidomide ne sont pas considérés comme de la chimiothérapie.)
    4. Toxicités cliniquement significatives et persistantes qui, selon l’investigateur, rendent le patient inapte à la transplantation
    5. Signes d'anticorps anti-HLA spécifiques au donneur pour l’USC de traitement #1 sélectionnée (MFI>3000 à HLA A, B, C, ou DRB1)
    6.Signes d'infection par le VIH ou sérologie positive pour le VIH
    7.Signe d'hépatite B ou d’hépatite C active déterminée par sérologie ou PCR
    8.Grossesse, indiquée par un sérum positif ou un test urinaire d’hormone chorionique gonadotrope humaine (HCG), ou allaitement
    9.Tumeur maligne active autre que celle pour laquelle la greffe d’USC est effectuée, dans les 12 mois précédant la participation. Une résection complète des cellules squameuses cutanées ou du carcinome basocellulaire ou du carcinome cervical in situ dans les 12 mois précédent la participation sera permis.
    10. Signes d'infections bactériennes, fongiques ou virales non contrôlées ou de maladies concomitantes graves qui, de l'avis de l’investigateur Principal, indiquent que le patient ne peut tolérer la transplantation
    11. Les patients montrant une présence de blastes leucémiques dans le système nerveux central (SNC)
    12. Les patients ayant un donneur apparenté ou non apparenté compatible HLA à 8/8 au niveau allèlique (ou selon les directives / recommandations locales si elles sont plus strictes) et facilement disponible (dont les cellules souches peuvent être collectées en temps opportun sans compromettre le résultat du receveur). Les patients ayant des donneurs haploidentiques ou des donneurs syngéniques ne seront pas exclus
    13. Greffe allogénique antérieure de cellules souches hématopoïétiques
    14. Allergie aux produits bovins, à la gentamicine ou à tout autre produit pouvant interférer avec le traitement
    15. Psychologiquement incapable de subir une greffe de moelle osseuse accompagnée d'un isolement strict ou d'antécédents documentés de non-conformité médicale et/ou de maladie psychiatrique et/ou de situations sociales qui limiteraient la conformité aux exigences de l'étude
    16. Participant à un autre essai clinique interventionnel ou ayant reçu un traitement expérimental dans les 30 jours précédant la date prévue de la randomisation, à moins que l'approbation documentée du promoteur n'ait été obtenue avant la randomisation
    E.5 End points
    E.5.1Primary end point(s)
    Assess the time to neutrophil engraftment following transplantation.
    Neutrophil engraftment is defined as achieving an absolute neutrophil
    count (ANC) ≥ 0.5 x 10^9/L on 3 consecutive measurements on
    different days with subsequent donor chimerism (≤10% host cells by
    peripheral blood chimerism or bone marrow chimerism if peripheral
    blood chimerism is not available). The day of neutrophil engraftment is
    designated as the first of the 3 consecutive measurements and must
    occur on or before 42 days post transplant (and also prior to infusion of
    any additional stem cell product).
    Évaluer le temps de prise de greffe de neutrophiles après la transplantation.
    La prise de greffe de neutrophiles est définie par l’atteinte d'un nombre absolu de neutrophiles (NAN) ≥ 0.5 x 10^9/L sur 3 jours consécutifs avec chimérisme subséquent du donneur (≤10 % de cellules hôtes par chimérisme du sang périphérique ou chimérisme de la moelle osseuse si le chimérisme du sang périphérique n'est pas disponible). Le jour de la prise de greffe de neutrophiles est désigné comme la première des 3 mesures consécutives et doit avoir lieu au plus tard 42 jours après la transplantation (et aussi avant la perfusion de tout produit supplémentaire de cellules souches).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Not relevant
    Non pertinent
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    •Incidence of grade 2/3 bacterial or invasive fungal infections by 100
    days following transplantation
    •Days alive and out of hospital in the first 100 days following
    transplantation
    •Platelet engraftment by 42 days following transplantation
    Tertiary Endpoint:
    •Non-relapse mortality by 210 days following randomization
    Exploratory Endpoints:
    •Neutrophil engraftment by 16 days following transplantation
    •Time from transplantation to platelet engraftment
    •Duration of primary hospitalization
    •Non-relapse mortality by 130 days and 15 months following
    randomization
    •Overall survival at 210 days and 15 months following randomization
    •Disease-free survival at 15 months following randomization
    •Neutrophil engraftment by 42 days following transplantation
    •Acute GvHD grade II-IV and III-IV by 100 days following transplantation
    •Chronic GvHD (mild/moderate/severe) by 180 days and 1 year
    following transplantation
    •Secondary graft failure by 1 year following transplantation
    •Grade 3 viral infections by 180 days and 1 year following
    transplantation
    •Safety and tolerability of NiCord® transplantation
    •Relapse by 15 months following randomization
    •Relapse mortality by 15 months following randomization
    •Immune reconstitution at 28, 70, 100, 180, and 365 days following transplantation
    •Supplemental immune reconstitution assessments at a central laboratory (optional)
    •Health-related quality of life
    •Long-term clinical outcomes up to 5 years following transplantation (optional)
    Paramètres secondaires :
    •Fréquence des infections bactériennes ou fongiques invasives de grade 2/3 dans les 100 jours suivant la transplantation
    •Nombre de jours en vie et hors de l'hôpital au cours des 100 premiers jours suivant la transplantation
    •Prise de greffe de plaquettes à 42 jours suivant la transplantation
    Paramètre tertiaire :
    •Mortalité non liée à une rechute 210 jours suivant la randomisation
    Paramètres exploratoires :
    •Prise de greffe de neutrophiles à 16 jours suivant la transplantation
    •Durée entre la transplantation et la greffe de plaquettes
    •Durée de l'hospitalisation principale
    •Mortalité non liée à une rechute à 130 jours et 15 mois suivant la randomisation
    •Survie globale à 210 jours et 15 mois suivant la randomisation
    •Survie sans récidive à 15 mois suivant la randomisation
    •Prise de greffe de neutrophiles à 42 jours suivant la transplantation
    •GvH aiguë Grade II-IV et III-IV à 100 jours suivant la transplantation
    •GvH chronique (légère/modérée/sévère) à 180 jours et 1 an suivant la transplantation
    •Échec secondaire de greffe à un an suivant la transplantation
    •Infections virales de grade 3 à 180 jours et 1 an suivant la transplantation
    •Innocuité et tolérabilité de la transplantation de NiCord®
    •Rechute à 15 mois suivant la randomisation
    •Mortalité par rechute à 15 mois suivant la randomisation
    •Reconstitution immunitaire à 28, 70, 100, 180 et 365 jours suivant la transplantation
    •Évaluations supplémentaires de la reconstitution immunitaire dans un laboratoire central (facultatif)
    •Qualité de vie liée à la santé
    •Résultats cliniques à long terme jusqu'à 5 ans suivant la transplantation (facultatif)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary EP
    day 100 following transplant
    day 100 following transplant
    day 42 following transplant
    Tertiary EP
    day 210 following random.
    Exploratory EP
    day 16 following transplant
    NR
    NR
    day 130 and 15 mon. following random.
    day 210 and 15 mon. following random.
    15 mon. following random.
    day 42 following transplant
    day 100 following transplant
    day 180 and 1 year following transplant
    1 year following transplant
    day 180 and 1 year following transplant
    NR
    15 mon. following random.
    15 mon. following random.
    day 28, 70, 100, 180 and 365 following transplant
    MultiPlex analyses (days 7, 14, 21, 28, 42, 56, 70, 100, 180 &day 365 visits and T cell receptor analysis (at screening and on days 100, 180
    and 365 visits)
    NR
    2,3,4&5 years post transplant
    Paramètres sec:
    100 j suivant le transplant
    100 premiers jour suivant le transplant
    42 j suivant le transplant
    tertiaire:
    210 j suivant la randomisation
    exploratoires:
    16j suivant le transplant
    NP
    NP
    130 j et 15 m suivant la randomisation
    210 j et 15 m suivant la randomisation
    15 m suivant la randomisation
    42j suivant le transplant
    100j suivant le transplant
    180j et 1 an suivant le transplant
    un an suivant le transplant
    180j et 1 an suivant le transplant
    NP
    15m suivant la randomisation
    15m suivant la randomisation
    28, 70, 100, 180 et 365 j suivant le transplant
    Analyses MultiPlex (visites des j 7,14,21,28,42,56,70,100,180 et 365) et analyse des récepteurs des lymphocytes T (au dépistage et visites des j 100,180 et 365)
    NP
    2, 3, 4 et 5 ans suivant le transplantation
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    une ou deux unités de sang de cordon ombilical non manipulées
    one or two Unmanipulated Umbilical Cord Blood Unit(s)
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    Italy
    Netherlands
    Portugal
    Singapore
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who enroll in the optional long-term follow up sub-study will be followed for up to 5 years post-transplantation.
    Les patients qui participent à la sous étude optionnelle de suivi à long terme feront l'objet d'un suivi jusqu'à cinq ans après la transplantation.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-06-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-07
    P. End of Trial
    P.End of Trial StatusCompleted
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